Technical Field
The disclosure relates to arsenoplatin and related compounds and methods for their use as chemotherapy agents.
Description of Relevant Prior Art
Cis-diamminedichloroplatinum(II) (“Cisplatin”) and arsenic trioxide (As2O3) are highly successful agents for treatment of cancer. Cisplatin is used in combination chemotherapy to treat ovarian, testicular, head, neck, and bladder cancers. Unfortunately, these and other cancers frequently develop resistance to this widely used agent and there are intensive efforts to develop new agents that overcome this resistance. Arsenic trioxide, which was discovered as a traditional Chinese medicine, is a front line treatment for acute promyelocytic leukemia and has also shown preliminary efficacy in the treatment of blood cancers such as multiple myeloma and myelodysplastic syndromes.
Both compounds induce apoptotic cell death, but through different pathways. Cisplatin reacts with DNA and causes intra- and inter-strand DNA cross-links. The principal component of aqueous solutions of As2O3 at pH 7, arsenous acid, at low concentrations reacts with and triggers degradation of key zinc-dependent regulatory proteins and inhibits angiogenesis, migration and invasion. At higher concentrations, arsenous acid triggers apoptosis through pathways that involve elevated levels of reactive oxygen species in mitochondria.
When combined, these agents can act synergistically in certain cisplatin sensitive and resistant ovarian and non-small lung carcinoma cells. The only example of a platinum adduct with arsenous acid in the literature emerged in efforts to develop efficient systems for loading As2O3 into liposomes with aquated forms of cisplatin.